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The detailed results of the Asymptomatic Carotid Atherosclerosis Study (ACAS) have been published. [1] Electrifying reports in the media suggested that 53% fewer strokes would occur if individuals with 60% or greater stenosis were submitted to endarterectomy. [2,3] The burning question is whether the evidence from this trial, and those preceding it, is sufficiently compelling to persuade any or all individuals with carotid stenosis, but free of any hemisphere and retinal symptoms, to have carotid endarterectomy. Based on a variety of population samplings, it is reasonable to estimate that approximately two million people are living in North America and Europe with asymptomatic lesions comparable with those studied in ACAS. [4-8]

Expansion of carotid endarterectomy to asymptomatic patients.

Carotid endarterectomy was introduced as a prophylaxis for ischemic stroke and was carried out initially on symptomatic patients. The recognition of the significance of carotid bruits, the development of noninvasive imaging of the neck arteries, and training of many surgeons capable of performing carotid endarterectomy spurred enthusiasm for its application to asymptomatic patients. The rationale for extending the procedure to patients before they have symptoms is reasonable. More patients present with stroke than with warning symptoms of a transient type. Carotid occlusion is the ultimate result of a progressing carotid stenosis. When occlusion occurs, with or without symptoms, it has the potential to deprive individuals who have poor collateral circulation of 25% of their cerebral circulation. The hope was that both stroke and occlusion might be obviated by early endarterectomy. Many surgical series, based on opinion and individual experience, began to appear, but the comparison with unoperated patients, as control subjects, was not convincing. [9,10]

Coronary artery bypass surgery is complicated often enough by cerebral ischemic events to promote the common practice of prophylactically removing the asymptomatic carotid stenosing lesion before or accompanying the cardiac procedure. This practice continues, although there is strong evidence that it adds additional risk for the individual requiring coronary bypass surgery and [11-17] overlooks the evidence that most cerebral complications arise from the heart, the pump, or the aortic site of the required shunt and occur equally in the territory of the stenosed as in the nonstenosed cerebral arteries.

There is a paucity of data about the proportion of carotid endarterectomies performed for asymptomatic disease. Available data suggest that one-quarter to one-half of the endarterectomies performed in the United States relate to asymptomatic patients. [18,19] The practice varies widely among institutions, practitioners, and countries. [20] Documentation from the Aspirin and Carotid Endarterectomy Trial (ACE), being conducted in 55 academic North American centers, indicates that 60% of the endarterectomies in 1994 and 1995 are being performed in asymptomatic patients (Taylor, personal communication). As the annual total of carotid endarterectomies performed in the United States alone is approaching 100,000 patients, it is of great importance to ensure its appropriate use and to be convinced that the facts justify what may prove to be a 10-fold increase in its application. [21]

Randomized trials in asymptomatic patients.

Carotid endarterectomy for asymptomatic patients has been evaluated in four randomized trials. No claim of benefit was made in the study entitled Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin (CASANOVA) [22] or in the Mayo Asymptomatic Carotid Endarterectomy study (MACE). [23] Both were small and suffered from study design problems. The Veterans Affairs Cooperative Study [24] reported a significant benefit in the surgical arm when transient cerebral ischemia was included with stroke to constitute the outcome events. Restricting the analyses to stroke alone indicated a small but statistically non-significant benefit that was eliminated when perioperative deaths were added into the analysis.

The results of the ACAS trial were more encouraging. [1] Of the 1,662 patients randomized into ACAS, 85 had a combined outcome of ipsilateral stroke or any perioperative stroke or any perioperative death in the 2.7 median years of follow-up; 52 occurred in the medical arm and 33 in the surgical arm. The risk of a combined outcome at 5 years, from the Kaplan-Meier event-free survival curves, was 11.0% in the medical arm and 5.1% in the surgical arm. From these risk estimates, the investigators claimed a relative risk reduction of 53%, at 5 years, favoring patients submitted to endarterectomy, but serious concerns interfere with the acceptance of this seemingly straightforward answer. The short median follow-up period of 2.7 years, compounded by the small number of patients who had completed 5 years of follow-up (9%, or approximately 150), lead to uncertainties in the interpretation of the Kaplan-Meier estimates of 5-year risk. The large relative risk reductions reported at 5 years are not supported by the cumulative patient experience at any time before year 5. The most striking example of this occurs for the combined outcome of major ipsilateral stroke or any perioperative major stroke or perioperative death Figure 1. Whereas the relative risk reduction at 5 years is reported to be 43% for this analysis, the relative risk reduction throughout the first 4.5 years is near zero. It is questionable whether a difference emerging at 5 years, due to just three outcome events, outweighs a consistently unfavorable surgical prognosis before this point. The wide 95% CI about the estimate of the relative risk reduction (minus 17 to 72%), the similar number of major outcome events in both treatment arms (surgical 21, medical 24), and the choice of statistical test add to the uncertainties surrounding this result.

Figure 1. These Kaplan-Meier curves show the probability that asymptomatic patients will survive free of a combined outcome of major ipsilateral stroke or any perioperative major stroke or perioperative death by treatment group. The solid line indicates medical patients, and the broken line, surgical patients. The estimated number of patients who remained event-free in each treatment group is shown at the bottom of the graph. Testing the difference between the medical and surgical risks of a combined outcome at 5 years yields a p of 0.12. Using a logrank test to compare treatments, across the entire Kaplan-Meier curves, yields a p of approximately 0.70. This Figure hasbeen modified from the original appearing in JAMA 1995;18:1425. [1]

The efficacy of carotid endarterectomy [1] was tested for statistical significance at only one point (5 years), using Greenwood's formula for the variances of the 5-year risk estimates. As the choice of time point is usually arbitrary, the danger is an exaggeration of treatment efficacy when the comparison is made at a time point with the largest difference between the Kaplan-Meier curves. Moreover, if the point in time is chosen post-hoc, the comparison may be invalidated. For these reasons, the testing of a treatment difference at only one time point along Kaplan-Meier curves is considered to be a ``bad method of analysis.'' [25] This approach to the analysis of clinical trials was abandoned over a decade ago in favor of methods (e.g., log-rank test, generalized Wilcoxon test) that make use of the cumulative patient experience across the entire Kaplan-Meier survival curves. Had a log-rank test been used in comparing the treatment arms, the statistical evidence for surgical efficacy in preventing major outcome events would have been much less certain (approximate p at the 0.70 level). This value is far removed from the reported p of 0.12, which is nonsignificant.

A similar concern is the report of a 53% relative risk reduction for the combined risk of ipsilateral stroke of any severity or any perioperative stroke or perioperative death at 5 years. [1] The relative risk reduction of these events is approximately 35% from year 2 until 4.5 years. Using a log-rank test to compare medical with surgical treatment would have resulted in a p of approximately 0.05 instead of the reported 0.004.

The ACAS results [1] can also be evaluated by comparing them with the effect of endarterectomy on symptomatic patients. A side-by-side comparison with the 2-year experience of patients from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [26] and from ACAS are shown in the Table 1. From the NASCET data, only six symptomatic patients with severe stenosis need be subjected to the risk of endarterectomy to prevent one stroke in a 2-year period, but 67 asymptomatic individuals must be submitted to the procedure to avoid one stroke in a 2-year period. The perioperative stroke and death rate was exceptionally low in ACAS. Even so, there is no apparent benefit from surgery until after the first year, and then the absolute risk reduction averages only 1.5% per year. If the perioperative rate in asymptomatic patients had been as high as the average in some large recent surveys and trials (4.5%, range 3.0 to 5.3%) [18,19,22,24] no real surgical benefit would have been achieved in the first 5 years postoperatively. The 5-year risk difference would not even achieve statistical significance Figure 2.

Figure 2. These Kaplan-Meier curves show the probability that asymptomatic patients will survive free of a combined outcome of ipsilateral stroke of any severity or any perioperative stroke or perioperative death by treatment group. The solid line indicates medical patients, and the broken line, surgical patients. The perioperative stroke and death rate for the top broken line is 2.3%, as reported by ACAS. [1] The bottom broken line is redrawn with a perioperative stroke and death rate of 4.5%. Clearly, a higher rate of surgical morbidity and mortality eliminates surgical benefit, even at 5 years. This Figure hasbeen modified from the original appearing in JAMA 1995;18:1425. [1]

Identification of asymptomatic patients at highest risk for stroke.

Given the narrow margin between medical and surgical benefit, it is important to identify asymptomatic individuals at the greatest risk of a stroke. In many retrospective studies, the degree of stenosis has been of paramount importance. [27-30] Large prospective studies have also reported that for higher grades of stenosis, individuals are at a greater risk of stroke than those with lesser degrees of stenosis. For individuals with less than 75 to 80% diameter-reducing stenosis, several studies have reported a stroke risk of less than 1.5% per year. [31-34] For patients with stenosis above this level, annual ipsilateral stroke rates of approximately 2.5% have been reported. [32]

The outlook was stenosis dependent in a longterm prognostic study of the asymptomatically diseased arteries in the European Carotid Surgery Trial (ECST). [35] Data from NASCET on the asymptomatic arteries support the prognostic importance of increasing degrees of stenosis Figure 3. From both studies, the data suggest that those with stenoses above 80% may be the individuals in whom interest should focus in future studies. They may prove to be the only group of asymptomatic patients in whom the risk of stroke is sufficiently high for endarterectomy to be beneficial.

Figure 3. Average annual risk (hazard rate) of ipsilateral stroke by degree of angiographically defined stenosis in the asymptomatic carotid artery of patients in NASCET. The data were derived from the medically treated, nonoperated, asymptomatic arteries of 270 patients. The curve was generated by fitting a Cox proportional hazards regression model to obtain average annual risks. The annual stroke risk drops below 3% when the degree of stenosis is under 70%.

Neither increasing risk of stroke nor benefit of endarterectomy was related to increasing stenosis in ACAS. [1] The small sample size, the small number of outcome events, and the reliance on Doppler ultrasound rather than conventional arteriography or even Duplex scanning may have precluded this study's ability to make this observation. The one analysis that examined the effect of stenosis upon outcome was restricted only to the patients who had prerandomization conventional arteriograms (N equals 642, 39% of the total sample), with 313 in the medical arm and 329 in the surgical arm. There were 27 outcome events (16 in the medical arm, 11 in the surgical arm). Despite this subgroup analysis being based on the patients where the degree of stenosis could be determined with the most accuracy, the finding that the risk of stroke for both the medically and surgically treated patients was higher in the lower deciles of stenosis was unexpected. Although this is a complete reversal of previous observations, [27-35] this paradox may be explained as a chance occurrence in the presence of insufficient data. The study concluded that for the reduction of 5-year risk of stroke ``there was no statistically significant gradation'' by degree of stenosis. However, the absence of proof is not a proof of absence.

Factors other than the degree of stenosis also affect the risk of stroke. Results from NASCET show a poorer prognosis for patients with the greatest number of risk factors than those with the fewest. [26] This association is observed for both symptomatic and asymptomatic arteries Figure 4. The striking annual risk of stroke in the symptomatic patients (15.8%) with severe disease and the highest risk profile is not matched by the asymptomatic patients (3.8%). The effect of risk profiles on patient prognosis was not examined in ACAS. [1] In ACAS, 64% of patients were hypertensive, 42% had evidence of myocardial ischemia, 26% smoked cigarettes, 23% had diabetes mellitus, and 20% had been subjected to previous carotid endarterectomy on the side contralateral to the asymptomatic lesion. Whether the frequency of these vascular risk factors is excessive compared with community-based populations with asymptomatic disease has not been addressed. The observations from Framingham [36] and from Evans County [37] on patients with cervical bruits have identified age, hypertension, and coronary artery disease as common phenomena indicative of increased risk of developing obliterative carotid artery disease.

Figure 4. Kaplan-Meier estimates of the average annual risk of ipsilateral stroke by the number of risk factors. The list of 16 risk factors that comprise the risk profile has been previously published. [26] The average annual risks of stroke corresponding to symptomatic 70-99% stenosed arteries were computed from 331 medically treated patients recruited into NASCET for their symptomatic artery. The same patients as in Figure 3 were used to compute the average annual risks corresponding to asymptomatic arteries. The striking annual risk of stroke in the symptomatic patients with severe disease is not matched by the asymptomatic patients, but the rising risk of stroke with rising risk profile remains evident.

Benefit for women was not found in ACAS. [1] The 5-year relative risk reduction for men was reported at 66% and for women at 17%. The explanation for this subgroup gender difference is uncertain. Part of the explanation may relate to a chance finding due to small numbers (568 women compared with 1,091 men) and part to the perioperative complication rate for women (3.6%) being more than double that for men (1.7%). Women were not studied in the Veterans' Administration (VA) trial. [24]

Shortcomings of the results from randomized trials on asymptomatic patients.

The randomized trials have yielded inconclusive and confusing results for the following reasons. First CASANOVA, [22] MACE, [23] and the VA trial [24] failed to find an improvement in long-term stroke-free survival. Second, the prominence given to the ``relative risk reduction'' rather than to the ``absolute risk difference'' in ACAS [1] has led to optimistic conclusions. Third, tests showing statistical significance have overlooked the compelling need to determine their clinical relevance and importance. The absolute difference between the medical and surgical risks is extremely narrow. Fourth, benefit will be obliterated if the exceedingly low operative morbidity and mortality of 2.3% in ACAS [1] is doubled to the national average of 4.5%. Fifth, major disabling strokes are not prevented by endarterectomy performed in asymptomatic patients. The average absolute benefit of surgery, in terms of disabling stroke in ACAS, [1] was less than 0.5% per year. This would be of consequence only if this operation could be done without perioperative risk. Finally, previous data have consistently identified that patients with stenosis in the upper deciles are at a greater risk of stroke and therefore are most likely to benefit from endarterectomy. This was not confirmed in ACAS [1] nor in the three smaller trials. [22-24] Conceivably, the importance to prognosis of the degree of stenosis, detected in NASCET, ECST, and in all the large long-term observational studies, could be less compelling than is our own interpretation of these data. More likely though, the small number of outcome events in ACAS lead to insufficient power to allow detection of clinically important differences in benefit between the patients with higher and lower degrees of stenosis. These distinctions may have been hampered also by the dependence of the ACAS upon measurements of stenosis by Doppler alone.

The dilemma persists.

Few vascular surgical procedures have been subjected to more retrospective case series or more single- and multicenter randomized clinical trials than carotid endarterectomy. This attention by the medical community is understandable. An estimated one million patients were subjected to the procedure between 1954 and 1985. Uncertainty persisted as to its appropriate application. [38-40] Three randomized trials have now reported benefit for endarterectomy in symptomatic subjects with severe stenosis measured by conventional arteriography who had experienced focal hemispheric or retinal symptoms. [26,41,42] Physicians are now obliged to consider endarterectomy for all comparable symptomatic patients.

Evidence for surgical benefit for asymptomatic carotid lesions continues to elude us. The management of any person with asymptomatic disease must concentrate on attention to the treatable risk factors with special emphasis given to hypertension, cigarette smoking, and the regulation of diabetes mellitus and cholesterol levels. Because patients with severe carotid artery stenosis are at high risk for myocardial infarction, their cardiac status should be evaluated and appropriate therapy initiated when indicated. The prophylactic daily use of aspirin is a reasonable strategy.

It has been suggested that endarterectomy be performed only ``on a subset of asymptomatic patients based on age, concomitant risk factors, progression of disease, and overall medical status of the individual.'' [43] Although this is reasonable speculation, there are no published data to prove that endarterectomy will be of clear benefit in any specific subgroup of asymptomatic patients. A recent decision analysis model proposes quite reasonably that greater benefit will accrue for younger patients (age approximate equal 55) than for older individuals. [44]

Individuals with the highest degrees of stenosis are reasonably expected to have a reduced stroke risk if the procedure is performed by surgeons with established low operative complication rates. Individuals with demonstrated progression of a known lesion may be promising candidates for endarterectomy, but the proof is lacking; the same is true for patients with asymptomatic stenosis in one carotid artery and a carotid occlusion in the artery on the other side. There is no clear evidence to support the recommendation of endarterectomy as a prelude to coronary artery bypass graft no matter how severe the degree of asymptomatic carotid stenosis. Finally, when patients with severe asymptomatic disease become symptomatic with TIA or minor stroke, they become candidates for further investigation that could lead to endarterectomy.

A large trial, the Asymptomatic Carotid Surgery Trial, has been launched in Europe [45] to supplement ACAS and the smaller VA asymptomatic trial, but it will be several years before these additional data become available. A set of complete guidelines for carotid endarterectomy should be regarded as ``work in progress.'' Until the required evidence is gathered together, the management of individuals with severe asymptomatic carotid stenosis is based unfortunately on empirical guidelines and pragmatic decisions. Population screening studies cannot be justified at present. The facts and figures do not support this strategy.

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